CN1314689C - Faropenem sodium synthesis method from reaction by-product - Google Patents
Faropenem sodium synthesis method from reaction by-product Download PDFInfo
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- CN1314689C CN1314689C CNB2005100442830A CN200510044283A CN1314689C CN 1314689 C CN1314689 C CN 1314689C CN B2005100442830 A CNB2005100442830 A CN B2005100442830A CN 200510044283 A CN200510044283 A CN 200510044283A CN 1314689 C CN1314689 C CN 1314689C
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Abstract
The present invention provides a method for synthesizing faropenem sodium from reaction by-products, which has the advantages of low cost, high output, easy reaction condition realization, etc.
Description
Technical field
The present invention relates to utilize the method for byproduct of reaction preparation method faropenem { 5R-(3R, 6R)-6-(1-hydroxyethyl)-7-oxygen 3-(tetrahydrochysene-2-furyl)-4 sulphur-1-azabicyclo [3.2.0] hept-2-ene" 2-carboxylic acid sodium }.
Background technology
Faropenem sodium (Faropenem Sodium) be 5R (3R, 6R)-common name of 6-(1-hydroxyethyl)-7-oxygen 3-(tetrahydrochysene-2-furyl)-4-sulphur-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid sodium, its structural formula is:
Faropenem sodium is the β-Nei Xiananleikangshengsu of penems, is developed by Japanese Suntory company, and 2000 first in Japan's listing, be first listing in such medicine stable to β-Nei Xiananmei, can oral injectable again Broad spectrum antibiotics.The same with other β-Nei Xiananleikangshengsu, Faropenem is applicable to the patient of different gradient of infection by suppressing the germicidal action of having synthesized of bacteria cell wall.Its curative effect and security have obtained fully certainly.
The main preparation methods of patent US4997829, US5830889, JP92041489 and the disclosed Faropenem sodium of EP410727 is by name with the 4-AA[chemistry: (3R, 4R, 1 ' R)-and 4-acetoxyl group 3-(1-tertiary butyl diformazan silica ethyl)-2-azetidinone] be raw material, synthesized Faropenem sodium through 6～9 steps respectively.
Chinese Journal of Pharmaceuticals (calendar year 2001,339～341 pages) has reported with 4-AA to be raw material, through intermediate compound I synthetic intermediate II, and the method for faropenem sodium synthesis (seeing shown in Figure 1) then.But this method easily produces the by product III of a certain amount of (about 10～15%), causes that the Faropenem sodium yield is lower, cost is higher.
Fig. 1.
Summary of the invention
Deficiency in view of the method for Chinese Journal of Pharmaceuticals (calendar year 2001,339～341 pages) faropenem sodium synthesis of reporting exists the invention provides a kind of method by the by product III faropenem sodium synthesis that is produced in the aforesaid method.This method has that cost is low, yield is high, reaction conditions is easy to advantages such as realization.
By product III is through Spectrum Analysis, and confirming as is the polymkeric substance of II, be a pair of suitable/anti-(Syn/Anti) isomer, have the basic framework of Faropenem, its ratio is 1: 1.
It is raw material that the present invention adopts III, at first is dissolved in solvent, directly reacts with 2 ethyl hexanoic acid sodium behind the deprotection base with deprotecting regent to obtain the Faropenem sodium crude product, obtains Faropenem sodium elaboration (seeing shown in Figure 2) through water/acetone recrystallization.
Fig. 2.
The present invention includes following steps:
A, III is dissolved in the solvent adds deprotecting regent and remove protecting group, temperature of reaction is 0 ℃～100 ℃, and the reaction times is 2～36 hours, and reaction system is standby through the routine extraction, after concentrating;
B, a is gone on foot the reaction of gained deprotection product and 2 ethyl hexanoic acid sodium solution, temperature of reaction is 0 ℃～40 ℃, and the reaction times is 2～36 hours, obtains crude product after filtration, and crude product obtains the Faropenem sodium elaboration through water/acetone recrystallization purifying.
The solvent that step a adopted is alkanes, aromatics, ethers, ester class or water, is specially in normal hexane, Skellysolve A, sherwood oil, benzene, toluene, tetrahydrofuran (THF), ether, ethyl acetate, the water one or more; The deprotecting regent that is adopted is a kind of in dilute hydrochloric acid or diluted hydrofluoric acid or the tetrabutyl ammonium fluoride.
" n " means 1～100 arbitrary integer as term as used herein.
Preparation technology of the present invention has rationally utilized intermediate III, and easy and simple to handle, controllability is strong, and three waste discharge is few, and has effectively improved the utilization ratio of 4-AA, has improved the preparation total recovery of Faropenem sodium.
Embodiment
Further elaborate preparation method of the present invention by following examples.
Embodiment 1: the preparation of Faropenem sodium
In there-necked flask, add the 35g compound III, after 400mL THF dissolving, add 60mL 15% hydrofluoric acid, be warming up to about 65 ℃ of reaction 18h, after the TLC monitoring reaction is complete, add 200mL water, use the 400mL ethyl acetate extraction, use the 100mL deionized water, 100mL unsaturated carbonate hydrogen is received solution, the saturated hydrogen sulfate of 100mL is received the washing of solution and 100mL saturated brine, collects organic phase, uses anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, deprotection product (faint yellow solid 20g), and be dissolved in the 150mL ether and transfer in the constant pressure funnel and be directly used in next step.
In above-mentioned diethyl ether solution, add 12g 2 ethyl hexanoic acid sodium, 4g triphenylphosphine, 1.8g tetrakis triphenylphosphine palladium, 50 ℃ of following stirring reactions, there are a large amount of flaxen solids to generate after 6 hours, filter, wash with tetrahydrofuran (THF), obtain solid 29g after the drying, be the Faropenem sodium crude product.
Above-mentioned 29g solid is separated with deionized water is dissolved, used the 300mL deionized water approximately, filter, filtrate is added in three mouthfuls of reaction flasks of 500mL, slowly add acetone under stirring, when being added to 100mL acetone approximately, it is muddy that solution begins to become, and stops to add, continue to stir allow its slowly crystallization spend the night, suction filtration is used washing with acetone, 40 ℃ of dryings, obtain white crystal 24g (purity: 99.0%, HPLC), be the Faropenem sodium elaboration, fusing point: 160-162 ℃.
Owing to described the present invention according to its special embodiment, some is modified and equivalent variations is conspicuous for the technician who is proficient in this field and comprises within the scope of the invention.
Claims (3)
1. method by the byproduct of reaction faropenem sodium synthesis is characterized in that:
1) described byproduct of reaction is any one or two kinds of in the following compound:
Wherein, TBS is meant that tertiary butyl dimethyl is silica-based, and n is meant 1～100 arbitrary integer;
2) this method may further comprise the steps:
A, be raw material with the byproduct of reaction, at first be dissolved in solvent, through the deprotection base, temperature of reaction is 0 ℃～100 ℃ with deprotecting regent, and the reaction times is 2～36 hours;
B, deprotection product and the reaction of 2 ethyl hexanoic acid sodium obtain the Faropenem sodium crude product, obtain the Faropenem sodium elaboration through water/acetone recrystallization.
2. method according to claim 1 is characterized in that solvent used among the step a is alkanes, aromatics, ethers, ester class or water.
3. method according to claim 1 is characterized in that deprotecting regent used among the step a is a kind of in dilute hydrochloric acid or diluted hydrofluoric acid or the tetrabutyl ammonium fluoride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100442830A CN1314689C (en) | 2005-08-22 | 2005-08-22 | Faropenem sodium synthesis method from reaction by-product |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100442830A CN1314689C (en) | 2005-08-22 | 2005-08-22 | Faropenem sodium synthesis method from reaction by-product |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1733771A CN1733771A (en) | 2006-02-15 |
| CN1314689C true CN1314689C (en) | 2007-05-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2005100442830A Expired - Fee Related CN1314689C (en) | 2005-08-22 | 2005-08-22 | Faropenem sodium synthesis method from reaction by-product |
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| CN (1) | CN1314689C (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0441489A (en) * | 1990-06-05 | 1992-02-12 | Suntory Ltd | Elimination of allyl group |
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2005
- 2005-08-22 CN CNB2005100442830A patent/CN1314689C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0441489A (en) * | 1990-06-05 | 1992-02-12 | Suntory Ltd | Elimination of allyl group |
Non-Patent Citations (1)
| Title |
|---|
| 法罗培南的合成 韩红娜等，中国医药工业杂志，第32卷第8期 2001 * |
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| CN1733771A (en) | 2006-02-15 |
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Assignee: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2010370000509 Denomination of invention: Faropenem sodium synthesis method from reaction by-product Granted publication date: 20070509 License type: Exclusive License Open date: 20060215 Record date: 20100908 |
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Assignee: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2010370000509 Date of cancellation: 20121226 |
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